4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues

Marco L Lolli; Cecilia Giordano; Darryl S Pickering; Barbara Rolando; Kasper B Hansen; Antonio Foti; Alberto Contreras-Sanz; Ahmad Amir; Roberta Fruttero; Alberto Gasco; Birgitte Nielsen; Tommy N Johansen

doi:10.1021/jm1001452

4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues

Marco L Lolli, Cecilia Giordano, Darryl S Pickering, Barbara Rolando, Kasper B Hansen, Antonio Foti, Alberto Contreras-Sanz, Ahmad Amir, Roberta Fruttero, Alberto Gasco, Birgitte Nielsen, Tommy N Johansen

24 Citations (Scopus)

Abstract

In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic α-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC₅₀ = 10 μM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	10
Pages (from-to)	4110-8
Number of pages	8
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm1001452
Publication status	Published - 27 May 2010

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Lolli, M. L., Giordano, C., Pickering, D. S., Rolando, B., Hansen, K. B., Foti, A., Contreras-Sanz, A., Amir, A., Fruttero, R., Gasco, A., Nielsen, B., & Johansen, T. N. (2010). 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues. Journal of Medicinal Chemistry, 53(10), 4110-8. https://doi.org/10.1021/jm1001452

4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues. / Lolli, Marco L; Giordano, Cecilia; Pickering, Darryl S et al.
In: Journal of Medicinal Chemistry, Vol. 53, No. 10, 27.05.2010, p. 4110-8.

Research output: Contribution to journal › Journal article › Research › peer-review

Lolli, ML, Giordano, C, Pickering, DS, Rolando, B, Hansen, KB, Foti, A, Contreras-Sanz, A, Amir, A, Fruttero, R, Gasco, A, Nielsen, B & Johansen, TN 2010, '4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues', Journal of Medicinal Chemistry, vol. 53, no. 10, pp. 4110-8. https://doi.org/10.1021/jm1001452

Lolli ML, Giordano C, Pickering DS, Rolando B, Hansen KB, Foti A et al. 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues. Journal of Medicinal Chemistry. 2010 May 27;53(10):4110-8. doi: 10.1021/jm1001452

Lolli, Marco L ; Giordano, Cecilia ; Pickering, Darryl S et al. / 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 10. pp. 4110-8.

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abstract = "In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic α-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC50 = 10 μM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.",

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AU - Giordano, Cecilia

AU - Pickering, Darryl S

AU - Rolando, Barbara

AU - Hansen, Kasper B

AU - Foti, Antonio

AU - Contreras-Sanz, Alberto

AU - Amir, Ahmad

AU - Fruttero, Roberta

AU - Gasco, Alberto

AU - Nielsen, Birgitte

AU - Johansen, Tommy N

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N2 - In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic α-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC50 = 10 μM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.

AB - In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic α-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC50 = 10 μM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.

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